Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection (acute bronchiolitis and pneumonia) in early infancy (Glezen et al., Amer. J. Dis. Child. 140:543, 1986; Holberg et al., Am. J. Epidemiol. 133:1135, 1991; “Fields Virology”, Fields, B. N. et al. Raven Press, N.Y. (1996), particularly, Chapter 44, pp 1313-1351 “Respiratory Syncytial Virus” by Collins, P., McIntosh, K., and Chanock, R. M.). Virtually all children are infected with RSV by the age of two years and 1-2% of all infected children require hospitalization (Holberg et al.; Parrott et al., Am. J. Epidemiol. 98:289, 1973). Outbreaks of RSV infection and lower respiratory tract deaths in infants and young children show a strong correlation (Anderson et al., J. Infect. Dis. 161:640, 1990), and mortality rates among hospitalized children range between 0.1-1% in the U.S. and Canada (Holberg et al.; Parrott et al.; Navas et al., J. Pediatr. 121:348, 1992; Law et al., Pediatr. Infect. Dis. J. 12:659, 1993; Ruuskanen and Ogra, Curr. Prob. Pediatr. 23:50, 1993). The consequences of RSV infection during infancy range from bronchiolitis or pneumonia to an increased risk for childhood asthma.
Despite intense efforts spanning the past four decades, the search for a safe and effective vaccine against RSV remains elusive. Initial RSV vaccines, including formalin-inactivated and live attenuated virus (reviewed in Murphy et al., Virus Res. 32:13, 1994), proved to be disappointingly non-protective and actually led to more severe lung disease in vaccinated children who subsequently acquired natural RSV infection. Immunopathological responses, especially involving inflammatory cell infiltration, may likely underlie RSV-mediated damage to lung tissue. Children who received the formalin-inactivated RSV vaccine developed high levels of virus-specific antibodies, but the antibodies had low levels of neutralizing activity (Murphy et al., J. Clin. Microbiol. 24:197, 1986) and failed to protect against infection by RSV (Kim et al., Am. J. Epidemiol. 89:422, 1969; Kapikian et al., Am. J. Epidemiol. 89:405, 1969; Fulginiti et al., Am. J. Epidemiol. 89:435, 1969; Chin et al., Virol. 1:1, 1969).
More recent efforts for development of an RSV vaccine have focused on subunit and recombinant methods. RSV has two major surface glycoproteins (designated F and G), which have been examined for use in potential vaccines. The F protein is involved in membrane fusion between the virus and target cell (Walsh and Hruska, J. Virol. 47:171, 1983), whereas the G protein is thought to mediate attachment of the virus to a cell receptor (Levine et al., J. Gen. Virol. 68:2521, 1987). Both RSV F and G proteins induce strong serum and mucosal immunity, which are important for protection against RSV infection (Glezen et al., 1986; Holberg et al.; Glezen et al., J. Pediatr. 98:708, 1981; Lamprecht et al., J. Infect. Dis. 134:211, 1976; Hemming et al., Clin. Microbiol. Rev. 8:22, 1995). Studies with mice have demonstrated that formalin-inactivated RSV and some G protein-encoding vaccinia recombinants prime for a harmful lung inflammatory response in which eosinophils are a prominent participant (Connors et al., J. Virol. 68:5321, 1994; Doherty, Trends Microbiol. 2:148, 1994; Waris et al., J. Virol. 70:2852, 1996; Graham et al., J. Immunol. 151:2032, 1993; Beasley et al., Thorax 43:679, 1988; Openshaw et al., Int. Immunol. 4:493, 1992).
Eosinophils and the eosinophil-attractant cytokine IL-5 are considered to be a feature of the so-called type 2 immune response, which has fostered the idea that immunization with RSV antigen has the potential to trigger type 2 responses depending on factors, such as the nature of specific viral immunogens and their route of presentation (Openshaw et al., 1992; Kakuk et al., J. Infect. Dis. 167:553, 1993; Openshaw and O'Donnell, Thorax 49:101, 1994). Recent work indicates that a portion of the conserved region of the RSV G protein is involved in protective immunity against RSV and in the generation of inflammatory responses, including the induction of eosinophilia (Sparer et al., J. Expt'l. Med. 187:1921, 1998; Tebbey et al., J. Expt'l. Med. 188:1967, 1998; Srikiatchachom et al., J. Virol. 73:6590, 1999; Varga et al., J. Immunol. 165:6487, 2000; Huang and Anderson, Vaccine 21:2500, 2003).
Hence, a need exists for identifying and developing compositions therapeutically effective against RSV infections, particularly those compositions that can function as a vaccine by eliciting protective immunity without any or with a reduced associated harmful pulmonary inflammation. Furthermore, there is a need for vaccine formulations that can be varied to protect against or treat for infection by different RSV immunogenic subtypes and subgroups. The present invention meets such needs, and further provides other related advantages.